2,6-methano-1,3-benzodiazocine compounds

ABSTRACT

Novel 2,6-methano-1,3-benzodiazocines, intermediates, processes for the preparation thereof, and methods for alleviating pain and for alleviating various memory dysfunctions characterized by a decreased cholinergic function, such as Alzheimer&#39;s disease, utilizing compounds or compositions thereof are disclosed.

This is a division of application Ser. No. 446,743 filed 12/6/89, nowU.S. Pat. No. 5,010,083, which is a continuation-in-part application ofapplication Ser. No. 174,274 filed Mar. 28, 1988 now abandoned.

This invention relates to 2,6-methano-1,3-benzodiazocines. Moreparticularly, this invention relates to 2,6-methano-1,3-benzodiazocinesof the formula ##STR1## wherein R¹ is selected from the group consistingof hydrogen, loweralkyl, arylalkylaminocarbonyl loweralkylcarbonyl,loweralkylaminocarbonyl, cycloalkylaminocarbonyl, loweralkoxycarbonyl,aryloxycarbonyl, and arylaminocarbonyl; R² and R³ are independentlyselected from the group consisting of hydrogen, loweralkyl,cycloalkylloweralkyl, arylloweralkyl, and loweralkenyl; R⁴ and R₅ areindedendently hydrogen or loweralkyl; Y is halogen, loweralkyl, nitro,amino, loweralkylcarbonylamino, arylcarbonylamino, formyl orloweralkylaminocarbonyl; and n is an integer having a value of zero or1; the geometrical isomers, optical antipodes or pharmaceuticallyacceptable acid addition salts thereof, which alone or in combinationwith inert adjuncts, are useful in alleviating pain and in alleviatingvarious memory dysfunctions characterized by a decreased cholinergicfunction, such as Alzheimer's disease.

Of particular interest are 2,6-methano-1,3-benzodiazocines of theformula ##STR2## wherein R¹ is hydrogen or loweralkyl; and R² and R³ areindependently selected from the group consisting of hydrogen,loweralkyl, cycloalkylloweralkyl, and arylloweralkyl. Subgeneric to the2,6-methano-1,3-benzodiazocines of this invention are Formula Icompounds wherein:

(a) R¹ is hydrogen;

(b) R¹ is loweralkyl;

(c) R¹ is a group of the formula --C(O)R⁶ wherein R⁶ is selected fromthe group consisting of loweralkyl, loweralkylamino, cycloalkylamino,arylalkylamino and arylamino;

(d) R¹ is loweralkoxycarbonyl or aryloxycarbonyl;

(e) R² is hydrogen;

(f) R² is loweralkyl;

(g) R² is cycloalkyloweralkyl;

(h) R² is arylloweralkyl;

(i) R³ is hydrogen;

(j) R³ is loweralkyl;

(k) R³ is arylloweralkyl;

(l) Y is chlorine or bromine;

(m) Y is amino or nitro;

(n) Y is loweralkylcarbonylamino or arylcarbonylamino;

(o) Y is formyl or loweralkylaminocarbonyl;

(p) n is zero; and

(q) n is 1.

In a further embodiment this invention relates to intermediates of theformula: ##STR3## wherein R¹ is loweralkyl; R² and R³ are independentlyhydrogen, loweralkyl, cycloalkylloweralkyl, loweralkenyl orarylloweralkyl; and R⁴ and R⁵ are independently hydrogen or loweralkyl.

As used throughout the specification and appended claims, the followingdefinitions shall apply:

"Loweralkyl" - a linear or branched, acyclic hydrocarbon radicalcontaining no unsaturation and having the formula --C_(x) H_(2x+1)wherein x is an integer having a value of 1 to 7, inclusive, such asmethyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl,4-heptyl, and the like.

"Loweralkoxy" - an acyclic organic radical of the formula --OC_(x)H_(2x+1) wherein x is an integer having a value of 1 to 7 inclusive,such as methoxy, ethoxy, 1- and 2-propoxy, 1,2-dimethylethoxy, 1-butoxy,1- and 2-pentoxy, 3-hexoxy, 4-heptoxy, and the like.

"Loweralkenyl" - a linear or branched, acyclic hydrocarbon radicalhaving one olefinic bond and represented by the formula --C_(x) H_(2x-1)wherein x is an integer having a value of 3 to 7, inclusive, such as2-propenyl, 3-butenyl, 3-pentenyl, 3-hexenyl, 6-heptenyl, and the like.

"Cycloalkyl" - a cyclic hydrocarbon radical of the formula --C_(x)H_(2x-1) wherein x is an integer having a value of 3 to 7, inclusive,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

"Aryl" - a phenyl group optionally substituted by up to 3 substituentseach of which is independently loweralkyl, loweralkoxy, halogen,trifluoromethyl, nitro or cyano. Unsubstituted and mono-substitutedphenyl groups are preferred.

"Halogen" - a member of the group consisting of fluorine, chlorine,bromine, and iodine radicals.

"Arylloweralkyl" - a loweralkyl group having an aryl substituentthereon.

"Cycloalkylloweralkyl" - a loweralkyl group having a cycloalkylsubstituent thereon.

"Loweralkylcarbonyl" - a group of the formula --C(O)C_(x) H_(2x+1)wherein x is an integer having a value of 1 to 7 inclusive.

"Loweralkoxycarbonyl" - a group of the formula --C(O)OAlk wherein Alk isa loweralkyl substituent as previously defined.

"Amino" - a group of the formula --NH₂.

"Aminocarbonyl" - a group of the formula --C(O)NH₂.

"Loweralkylamino" - an amino group having a loweralkyl substituentthereon.

"Loweralkylaminocarbonyl" - an aminocarbonyl group substituted at thenitrogen atom thereof by a loweralkyl group.

"Loweralkylcarbonylamino" - a group of the formula --NHC(O)Alk whereinAlk is a loweralkyl substituent as previously defined.

"Cycloalkylamino" - an amino group having a cycloalkyl substituentthereon.

"Cycloalkylaminocarbonyl" - an aminocarbonyl group substituted at thenitrogen atom thereof by a cycloalkyl group.

"Arylamino" - an amino group having an aryl substituent thereon.

"Arylaminocarbonyl" - an aminocarbonyl group substituted at the nitrogenatom thereof by an aryl group.

"Arylcarbonylamino" - a group of the formula --NHC(O)Ar wherein Ar is anaryl substituent as previously defined.

"Aryloxycarbonyl" - a group of the formula --C(O)OAr wherein Ar is anaryl substituent as previously defined.

The 2,6-methano-1,3-benzodiazocines of this invention are synthesized bythe processes illustrated in the Reaction Schemes which follow.

Reaction Scheme A details the preparation of an alkyl ester quinolinone7. As illustrated, 5-hydroxy-2-nitrobenzaldehyde 1 is reacted withmalonic acid to produce 3-(5-hydroxy-2-nitro)phenyl-2-propenoic acid 2which is converted to 3-(5-methoxy-2-nitrophenyl)-2-propenoic acidmethyl ester 3 and then reduced. The resulting aniline derivative 4 isthen converted to a malonamide ester 5, which is cyclized to aquinolinone diester 6, and thereafter decarboxylated to thecorresponding mono-ester derivative 7.

The reaction of 5-hydroxy-2-nitrobenzaldehyde 1 with malonic acid toproduce propenoic acid 2 is known in the art. Typically the reaction isconducted in the presence of piperidine at from about room temperatureto the reflux temperature of the solvent medium. See, for example, U.S.Pat. No. 4,424,150. The resulting acid 2 is converted to the ester 3 bytreatment with dimethyl sulfate in the presence of an alkali metalcarbonate (e.g. potassium carbonate, sodium carbonate, and the like;potassium carbonate being preferred). The esterification is ordinarilyconducted in a non-reactive organic solvent such as, for example,acetone, 2-butanone or dimethylformamide, at from about room temperatureto the reflux temperature of the solvent medium. Preferably, thereaction is conducted in acetone under reflux conditions. Reduction ofthe nitro group of the ester 3 to afford the aniline derivative 4 isaccomplished by treatment with an appropriate reducing agent (e.g.dithionite, iron, zinc, and the like, or, aqueous titanium trichloridein the presence of ammonium acetate). Desirably, the reduction iscarried out in the presence of a suitable organic solvent at atemperature of from about 0° C. to the reflux temperature of thereaction medium.

As further illustrated in Reaction Scheme A, loweralkyl functionalitymay be introduced at the 3-position of the propenoic acid ester 3 byconverting the nitrobenzaldehyde 1 to the corresponding ketone 1a andthereafter proceeding with the reaction sequence previously described.Ketone formation may be effected by treating the nitrobenzaldehyde 1with a Grignard reagent (e.g. methylmagnesium bromide, ethylmagnesiumbromide, methylmagnesium chloride, ethylmagnesium chloride, and thelike) to form an alcohol intermediate which is thereafter oxidized tothe ketone 1a. The Grignard reaction is generally conducted at atemperature of from about 0° C. to about 100° C. under anhydrousconditions in the presence of a organic solvent. Suitable solventsinclude ethers such as dioxane, tetrahydrofuran, and the like. Oxidationof the alcohol intermediate may be accomplished by treatment with asuitable oxidizing agent, for example, pyridinium chlorochromate.

Conversion of the amino-substituted propenoic acid ester 4 to themalonamide ester 5 is accomplished by treatment with ethyl malonylchloride in the presence of a suitable base (e.g. polyvinylpyridine,triethylamine, pyridine, and the like). The reaction is ordinarilycarried out in a non-reactive organic solvent at a temperature of fromabout 0° C. to about 25° C., preferably at about 0° C. Among thesuitable solvents there may be mentioned halocarbons such as, forexample, dichloromethane, trichloromethane, 1,1-dichloroethane,1,2-dichloroethane, and the like. Dichloromethane is the preferredsolvent. Cyclization of the resulting malonamide ester 5 to thequinolinone diester 6 is achieved by reaction with an alkali metalalkoxide (e.g. sodium methoxide, sodium ethoxide, potassium methoxide,and the like; sodium methoxide being preferred) in the presence of asuitable alkanol (e.g. methanol, ethanol, n-butanol, and the like;methanol being preferred) at a temperature of from about 40° C. to thereflux temperature of the solvent medium. Preferably, refluxtemperatures are employed in the cyclization reaction. Decarboxylationof the quinolinone diester 6 at temperatures of from about 150° C. toabout 160° C. affords the mono-ester derivative 7. The decarboxylationis typically conducted in a wet dipolar aprotic organic solvent (e.g.hexamethylphosphoramide, dimethylsulfoxide, dimethylformamide, and thelike) in the presence of an alkali metal halide (e.g. potassiumchloride, sodium chloride, sodium bromide, and the like; sodium chloridebeing preferred).

Loweralkyl functionality can be introduced at the nitrogen atom of themono-ester 7 by treatment with an alkali metal hydride (potassiumhydride, sodium hydride, and the like; sodium hydride being preferred)followed by a loweralkyl halide (e.g. methyl bromide, methyl iodide,ethyl bromide, and the like) to afford the loweralkyl-substitutedderivative 8. The alkylation is ordinarily conducted in the presence ofa suitable solvent, (e.g. polar solvents such as, for example,dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide, and thelike; dimethylformamide being preferred), at temperatures of from about0° C. to about 25° C.

Alternatively, substitution at the nitrogen atom of the quinolinone maybe accomplished by prior alkylation of the aminophenyl-substitutedderivative 4. Conversion of the resulting propenoic acid ester 4a to themalonamide ester 5a followed by cyclization to the diester 6a is aspreviously described. Treatment of the diester 6a with a suitable base(e.g. an alkali metal hydride such as sodium hydride), followed byalkylation with a lower alkyl halide (e.g. methyl iodide) gives thecorresponding lower alkyl derivative 6b, which is decarboxylated aspreviously described to the quinolinone 8a.

As illustrated in Reaction Scheme B the parent system of the Formula Icompounds of this invention i.e., a 2,6-methano-1,3-benzodiazocine 11 isproduced by converting a 1-substituted quinolinone 8a to an aldehydederivative 9 which is reacted with a primary amine under reductiveconditions to afford a 4-[(amino)ethyl]-2(1H)-quinolinone 10 and thencyclized to the benzodiazocine 11.

Conversion of the mono-ester derivative 8a to the corresponding aldehydederivative 9 can be accomplished by treatment with a complex of sodiumbis(2-methoxyethoxy)aluminum hydride and morpholine. The reaction isordinarily conducted in the presence of a suitable solvent (e.g.aromatic hydrocarbons such as, for example, benzene, toluene, xylene,and the like; toluene being preferred) at a temperature of from about-25° C. to about 0° C., preferably from about -20° C. to about -25° C.

Alternatively, the aldehyde derivative 9 can be produced by reducing theester 8a to an alcohol derivative 9a which is then oxidized to thealdehyde 9. Treatment of the ester 8a with an appropriate reducingagent, such as, for example, sodium bis(2-methoxyethoxy)aluminumhydride, lithium borohydride, and the like; lithium borohydride beingpreferred, provides a convenient means of forming the alcohol derivative9a. The reduction is typically conducted in a non-reactive organicsolvent, at a temperature of from about 25° C. to the reflux temperatureof the solvent medium. Suitable solvents include ethereal solvents suchas, for example, diethyl ether, dioxane, 1,2-dimethoxyethane,tetrahydrofuran, and the like; tetrahydrofuran being preferred.Oxidation of the alcohol derivative 9a to the aldehyde derivative 9 isaccomplished by any of a number of synthetic procedures which are wellknown in the art. For example, treatment of the alcohol derivative 8awith a complex of chromium (VI) oxide and pyridine (i.e., CrO₃ •2C₅ H₅N) at room temperature in a halogenated hydrocarbon such as methylenechloride or dichloroethane.

Reductive amination of the aldehyde derivative 9 is accomplished bytreatment with a compound of the formula R³ NH₂ •HCl wherein R³ isselected from the group consisting of loweralkyl, cycloalkylloweralkyl,and arylloweralkyl as previously described, and a suitable reducingagent (e.g. alkali metal cyanoborohydrides such as potassiumcyanoborohydride, sodium cyanoborohydride, and the like; sodiumcyanoborohydride being preferred). The reaction is generally conductedin an alkanol solvent (e.g. methanol, ethanol, n-butanol, and the like,methanol being preferred) at about room temperature. Cyclization of theamine 10 to the 8-methoxy-2,6-methano-1,3-benzodiazocine 11 isaccomplished by treatment with an alkali metal (e.g. potassium, sodium,and the like; sodium being preferred). The cyclization is generallyconducted in the presence of an alkanol solvent (e.g. methanol, ethanol,n-butanol, and the like, n-butanol being preferred) at refluxtemperatures.

As illustrated in Reaction Scheme C the 2,6-methano-1,3-benzodiazocine11 may be furnished with a variety of functional groups at the8-position thereof. For example, conversion of the8-methoxy-1,3-benzodiazocine 11 to the corresponding8-hydroxy-substituted derivative 12 followed by treatment with anisocyanate of the formula O═C═NR wherein R is loweralkyl, cycloalkyl,arylalkyl or aryl provides a 2,6-methano-1,3-benzodiazocine 13 whereinR¹ is loweralkylaminocarbonyl, cycloalkylaminocarbonyl,arylalkylaminocarbonyl or arylaminocarbonyl. Conversion of the8-methoxy-2,6-methano-1,3-benzodiazocine 11 to the hydroxy-substitutedderivative 12 can be accomplished by treatment with a dealkylating agentsuch as for example, boron tribromide, boron trichloride, aluminumchloride, and the like. In general, the dealkylation is conducted in thepresence of a suitable solvent (e.g. a halogenated hydrocarbon such aschloroform, dichloromethane, and the like) at a temperature of fromabout -20° C. to about room temperature. Reaction of thehydroxy-substituted derivative 12 with an isocyanate is ordinarilycarried out at temperatures of from about 0° C. to about 80° C. in anappropriate solvent (e.g. halogenated hydrocarbons such as chloroform).Alternatively, reaction of the phenol with 1,1'-carbonyldiimidazole,followed by addition of a primary or secondary amine of the formulaRNHR⁷, wherein R is as previously described and R⁷ is hydrogen orloweralkyl provides the desired carbamates.

Alternatively, compounds where R¹ is loweralkylaminocarbonyl,arylalkylaminocarbonyl, cycloalkylaminocarbonyl or arylaminocarbonyl canbe prepared in the following manner. The 8-hydroxy substitutedderivative 12 is reacted with triisopropylsilyltrifluoromethanesulfonate and 2,6-lutidine to afford a silyl ether. To the silyl etheris added tetra-n-butyl ammonium fluoride solution and lithium chlorideprior to the reaction with the isocyanate. The reaction is typicallyconducted at temperatures of from about 0° C. to room temperature in anappropriate solvent such as tetrahydrofuran.

Formula I compounds wherein R¹ is loweralkylcarbonyl are produced byreacting the 8-hydroxy-substituted derivative 12 with an anhydride ofthe formula R⁶ C(O)OC(O)R⁶ (e.g., acetic anhydride). The acylation isgenerally conducted at a temperature of from about 0° C. to about 55°C., preferably from about 0° C. to about 30° C., in a halocarbon solvent(e.g., methylene chloride, dichloroethane, chloroform, and the like;methylene chllride being preferred). Desirably, the reaction isconducted in the presence of a suitable basic catalyst (e.g.,N,N-dimethylaminopyridine, lutidine, collidine, and the like;N,N-dimethylaminopyridine being preferred).

Reaction of the 8-hydroxy-substituted derivative 12 with an alkyl- oraryl carbonate (e.g. methyl carbonate, phenyl carbonate, and the like)provides a means of furnishing a Formula I compound wherein R¹ isloweralkoxycarbonyl or aryloxycarbonyl. The reaction is ordinarilyconducted in an ethereal solvent (tetrahydrofuran being preferred) inthe presence of an alkali metal hydride such as, for example, sodiumhydride, potassium hydride, and the like. ##STR4##

To provide a Formula I 2,6-methano-1,3-benzodiazocine wherein R¹ isloweralkyl (other than methyl), it is recommended that the5-hydroxy-2-nitrobenzaldehyde 1 be reacted with a loweralkyl halide(e.g. isopropyl iodide, ethyl chloride, and the like) to form a5-alkoxy-2-nitrobenzaldehyde which is then reacted as previouslydescribed to afford a 2,6-methano-1,3-benzodiazocine having an alkoxygroup at the 8-position thereof.

The introduction of a substitutent Y to the compounds of this inventionmay be effected by a variety of mechanisms tailored to the particularfunctional group involved. For example, the reaction of a2,6-methano-1,3-benzodiazocine 13 with a halogenating agent (e.g.N-bromosuccinimide, N-chlorosuccinimide, and the like) is recommended asa means of forming a Formula I compound 14 wherein Y is halogen.Suggested solvents for the halogenation reaction include alkanols andhalogenated hydrocarbons (e.g., methanol, chloroform, dichloroethane,and the like; methanol being preferred). Halogenation of an esterderivative of an 8-hydroxy-2,6-methano-1,3-benzodiazocine 12 followed byconversion of the halogenated ester to the corresponding 8-olderivative, being a convenient means of directing halogenation at the10-position of the compounds of this invention.

Treatment of an acetate or carbamate derivative of a benzodiazocine 13with nitropyridium- or nitronium tetrafluoroborate in a suitable solvent(e.g. acetonitrile) provides as a means of furnishing Formula Icompounds wherein Y is nitro. Reduction of the resultant nitroderivative affords the corresponding amine. Treatment of the amine withan acid anhydride (e.g. acetic anhydride, benzoic anhydride, and thelike) and an appropriate acylation catalyst (e.g.4-dimethylaminopyridine) is suggested as a means of formingloweralkylcarbonylamino or arylcarbonylamino derivatives 14.

To furnish a Formula I compound wherein Y is formyl orloweralkylaminocarbonyl, a10-bromo-1,2,3,4,5,6-hexahydro-1-methyl-2,6-methano-1,3-benzodiazocin-8-ol15 may be treated with triisopropylsilyl triflate to form a silyl etherderivative 16 which in turn is treated with an appropriate organolithiumcompound (e.g. t-butyl lithium) to afford an organolithium derivative 17from which the desired formyl derivative 18 or loweralkylaminocarbonylderivative 19 may be produced. See Reaction Scheme D.

The reaction of the10-bromo-1,2,3,4,5,6-hexahydro-1-methyl-2,6-methano-1,3-benzodiazocin-8-ol15 with triisopropyl triflate is typically conducted in a halogenatedhydrocarbon solvent (dichloromethane being preferred) in the presence of2,6-dimethylpyridine. The reaction is generally conducted at atemperature of from about 0° C. to about 25° C. Treatment of the silylether derivative 16 formed by this reaction with an organolithiumderivative such as t-butyl lithium is generally conducted at reducedtemperature in an ethereal solvent (e.g., tetrahydrofuran). Formyl andloweralkylaminocarbonyl derivatives are produced by treatment of theresultant organolithium derivative 17 with dimethylformamide or aloweralkylisocyanate respectively. Deprotection of the resultant formyl-and loweralkylaminocarbonyl substituted silyl ethers 18 and 19, such asby treatment with tetrabutylammonium fluoride, affords the correspondingphenols 20 and 21.

Included among the compounds of this invention are the following;

1,2,3,4,5,6-hexahydro-8-methoxy-2,6-methano-1,3-benzodiazocine;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,acetate;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,methyl carbamate;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,cyclopropyl carbamate;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,phenyl carbamate;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,4-fluorophenyl carbamate;

3-benzyl-1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-2,6-methano-1,3-benzodiazocine;

3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-2,6-methano-1,3-benzodiazocine;

1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-3-(3-methyl-2-butenyl)-2,6-methano-1,3-benzodiazocine;

1,2,3,4,5,6-hexahydro-8-methoxy-1,3,6,11-tetramethyl-2,6-methano-1,3-benzodiazocine;

9-chloro-1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine;

10-chloro-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazoin-8-ol;

9-bromo-1,2,3,4,5,6-hexhahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol;

10-bromo-1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine;

10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol;

3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-1-methyl-2,6-methano-1,3-benzodiazocin-8-ol;

1,2,3,4,5,6-hexahydro-1-methyl-3-(2-phenylethyl)-2,6-methano-1,3-benzodiazocin-8-ol;

1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-3-(2-phenylethyl)-2,6-methano-1,3-benzodiazocine;

1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-10-nitro-2,6-methano-1,3-benzodiazocine;

10-amino-1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine;

10-formyl-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol;

1,2,3,4,5,6-hexahydro-8-methoxy-1,3,10-trimethyl-2,6-methano-1,3-benzodiazocine;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-10-(N-methylamino)carbonyl-2,6-methano-1,3-benzodiazocin-8-ol;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,phenyl carbonate;

1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,ethyl carbonate;

10-benzamido-1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine;

1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine;and

10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olacetate.

The 2,6-methano-1,3-benzodiazocines of this invention are useful asanalgetics due to their ability to alleviate pain in mammals. Theprocedure employed to determine analgetic activity is a modification ofthe phenyl-p-quinone writhing assay in mice, a standard assay foranalgesia [Proc. Soc. Exptl. Bio. Med., 95 729 (1957)]. Pursuant to themodified procedure, phenyl-p-benzoquinone (Eastman, 12.5 mg) isdissolved in 5 ml of 95% ethanol and the solution is diluted to a totalvolume of 100 ml with distilled water. The solution is administered tothe subject mice intraperitoneally at a dose of 10 ml per kg of bodyweight. A characteristic "writhe", an inward rotation of one or morefeet with twisting and turning of the trunk, drawing in of the abdominalwall, lordosis and arching of the back, is produced.

A total of 28 male mice (Charles River, CD-1), weighing 18 to 30 grams,are employed for a time response. The subject animals receive food andwater ad libitum. Test compounds are dissolved in distilled water, orsuspended in distilled water containing one drop of a suitablesurfactant, such as Tween-80.

Four groups of five animals (20 animals) are given the test compoundsubcutaneously or orally (p.o.) at 15, 30, 45, and 60 minutes prior toadministration of the phenyl-p-quinone. A control group (2 animals pergroup) receive an equal volume of the vehicle. After the administrationof the phenyl-p-quinone, the mice are placed separately in one literbeakers, and after five minutes, are observed for ten minutes. Thenumber of writhes for each animal is recorded. The following formula isused to compute the percent inhibition: ##EQU1##

The time period with the greatest percent of inhibition is consideredthe peak time. A dose range determination is generally reserved forthose compounds which inhibit writhing by greater than 65-70% at thescreening dose. A dose range determination is run in the same manner asthe time response except 10 animals per group are tested at the peaktime of test drug activity. Fifty animals, four test drug groups, and avehicle control are employed. Animals are dosed and tested in arandomized manner. A calculated ED₅₀, i.e., the calculated dose at which50% inhibition of writhing is produced, is determined by a computerlinear regression analysis. The calculated subsutaneous (s.c.) doseeffecting an approximately 50% inhibition of writhing (ED₅₀) in miceproduced in this assay is as follows:

    ______________________________________                                                               Analgesic Activity                                                            (Inhibition of                                                                Writhing)                                              Compound               ED.sub.50 mg/kg, s.c.                                  ______________________________________                                        1,2,3,4,5,6-hexahydro-8-methoxy-                                                                     10.2                                                   dimethyl-2,6-methano-1,3-benzodiazocine                                       1,2,3,4,5,6-hexahycro-1,3-dimethyl-                                                                  0.70                                                   2,6-methano-1,3-benzodiazocin-8-ol                                            1,2,4,5,6-hexahydro-1,3-dimethyl-                                                                    0.74                                                   2,6-methano-1,3-benzodiazocin-8-ol acetate                                    10-bromo-1,2,3,4,5,6-hexahydro-1,3-                                                                  1.9                                                    dimethyl-2,6-methano-1,3-benzodiazocin-8-ol                                   pentazocine            1.3                                                    ______________________________________                                    

Analgesia production is achieved when the2,6-methano-1,3-benzodiazocines of this invention are administered to asubject requiring such treatment as an effective oral, parenteral orintravenous dose of from 0.1 to 50 mg/kg of body weight per day. It isto be understood, however, that for any particular subject, specificdosage regimens should be adjusted according to the individual need andthe professional judgment of the person administering or supervising theadministration of the aforesaid compound. It is further understood thatthe dosages set forth herein are exemplary only and that they do not, toany extent, limit the scope or practice of the invention.

The compounds of the present invention are also useful in the treatmentof various memory dysfunctions characterized by decreased cholinergicfunction, such as Alzheimer's disease.

This utility is manifested by the ability of these compounds to inhibitthe enzyme acetylcholinesterase and thereby increase acetylcholinelevels in the brain.

CHOLINESTERASE INHIBITION ASSAY

Cholinesterases are found throughout the body, both in the brain and inserum. However, only brain acetylcholinesterase (AChE) distribution iscorrelated with central cholinergic innervation. This same innervationis suggested to be weakened in Alzheimer patients. Therefore, specificinhibitors of brain AChE (as opposed to serum cholinesterase) will giverise to fewer side effects and thus lower toxicity than physostigmine(an unspecific cholinesterase inhibitor). We have determined in vitroinhibition of acetylcholinesterase activity in rat striatum according tothe method described below. Results of some of the compounds of thisinvention as well as those of physostigmine are presented below.

IN VITRO INHIBITION OF ACETYLCHOLINESTERASE ACTIVITY IN RAT STRIATUM

Acetylcholinesterase (AChE), which is sometimes called true or specificcholinesterase, is found in nerve cells, skeletal muscle, smooth muscle,various glands and red blood cells, AChE may be distinguished from othercholinesterases by substrate and inhibitor specificities and by regionaldistribution. Its distribution in the brain correlates with cholinergicinnervation and subfractionation shows the highest level in nerveterminals.

It is generally accepted that the physiological role of AChE is therapid hydrolysis and inactivation of acetylcholine. Inhibitors of AChEshow marked cholinomimetic effects in cholinergically-innervatedeffector organs and have been used therapeutically in the treatment ofglaucoma, myasthenia gravis and paralytic ileus. However, recent studieshave suggested that AChE inhibitors may also be beneficial in thetreatment of Alzheimer's dementia.

The method described below was used in this invention for assayinganticholinesterase activity. This is a modification of the method ofEllman et al., Biochem. Pharmacol. 7, 88 (1961).

PROCEDURE

A. Reagents

1. 0.05M Phosphate buffer, pH 7.2

(a) 6.85 g NaH₂ PO₄ •H₂ O/100 ml distilled H₂ O

(b) 13.40 g Na₂ HPO₄ •7H₂ O/100 ml distilled H₂ O

(c) add (a) to (b) until pH reaches 7.2

(d) dilute 1:10

2. Chromogen-substrate buffer

(a) 9.9 mg 5,5-dithiobisnitrobenzoic acid (DTNB) (0.25 mM)

(b) 99 mg s-acetylthiocholine chloride (5 mM)

(c) q.s. to 100 ml with 0.05M phosphate buffer, pH 7.2 (reagent 1)

3. For most assays, a 2 mM stock solution of the test drug is made up ina suitable solvent and serially diluted such that the finalconcentration in the preincubation step ranges from 10⁻³ to 10⁻⁶ M.Different concentrations may be used depending on the potency of thedrug.

B. Tissue Preparation

Male Wistar rats are decapitated, brains rapidly removed, corporastriata dissected free, weighed and homogenized in 19 volumes(approximately 7 mg protein/ml) of 0.05M phosphate buffer, pH 7.2 usinga Potter-Elvehjem homogenizer. A 50 microliter aliquot of the homogenateis added to 50 microliter vehicle of various concentrations of the testdrug and preincubated for 10 minutes at room temperature.

C. Assay

1. For routine IC₅₀ determinations the Abbott Bichromatic Analyzer,ABA-100, is used to determine acetylcholinesterase activity.

Instrument Settings

    ______________________________________                                                Filter: 450-415                                                               Incubation temperature: 30° C.                                         Decimal point: 0000                                                           Analysis time: 5 minutes                                                      Carousel Revolution: 3                                                        Reaction direction                                                            down                                                                          endpoint                                                                      Syringe plate: 1:101 dilution                                         ______________________________________                                    

Following the 10 minuted preincubation of the tissue (enzyme) with theinhibitor, the samples are mixed with the substrate chromogen buffer bythe ABA-100. Using the indicated instrument settings the ABA-100automatically reads the color reaction and prints out the results inenzyme units after 15 minutes.

2. The enzyme activity can also be measured with a Gilford 250spectrophotometer. This method is used for more accurate kineticmeasurements.

    ______________________________________                                        Instrument settings                                                           ______________________________________                                        Lamp:             visible                                                     Filter:           no filter                                                   Wavelength:       412 nm                                                      Slit width:       0.2 mm                                                      Selection:        small aperature                                             Calibrated absorbance:                                                                          1.0 unit full scale                                         Chart speed:      0.5 cm/min.                                                 ______________________________________                                        Reagents are added to the reference and sample side of a split                curvette as follows:                                                          Reference         Sample                                                      ______________________________________                                        0.8 ml 0.05 M phosphate buffer                                                                  0.8 ml 0.05 M phosphate buffer                              0.8 ml Chromogen-substrate                                                                      0.8 ml Chromogen-substrate                                  buffer            buffer                                                                        10 microliter enzyme                                                          (tissue homogenate)                                         ______________________________________                                    

The uninhibited activity of the enzyme (tissue homogenate) is firstdetermined. Test drugs are made up in a suitable solvent and added insuitable dilutions to the buffer vehicle. The reaction rate isdetermined by the slope of the recorded absorbance change. The actualrate (moles/liter/min) can be calculated as described in the followingformula

    rate (moles/liter/min)=slope/(1.36×10.sup.4)

INHIBITION OF BRAIN ACETYCHOLINESTERASE ACTIVITY

    ______________________________________                                                               (10.sup.-6 M)                                                                 Inhibitory                                             Compound               Concentration                                          ______________________________________                                        1,2,3,4,5,6-Hexahydro-1,3-dimethyl-2,6-                                                              10.7                                                   methano-1,3-benzodiazocin-8-ol, cyclohexyl                                    carbamate                                                                     1,2,3,4,5,6-Hexahydro-1,3-dimethyl-2,6-                                                              .058                                                   methano-1,3-benzodiazocin-8-ol, methyl                                        carbamate fumarate                                                            [2S-[2b,6b]] and [2R-[2a,6a]]-1,2,3,4,5,6-                                                           8.7                                                    Hexahydro-2,6-methano-1,3-benzodiazocin-8-                                    ol, S-α-methylbenzylcarbamate salicylate                                Tacrine (standard)     5.7                                                    ______________________________________                                    

2,6-Methano-1,3-benzodiazocines of this invention, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience, increased solubility and the like. Preferredpharmaceutically acceptable acid addition salts include salts of mineralacids, for example, hydrochloric acid, sulfuric acid, nitric acid andthe like, salts of monobasic carboxylic acids such as, for example,acetic acid, propionic acid and the like, salts of dibasic carboxylicacids such as, for example, carboxysuccinic acid, citric acid and thelike.

Effective quantities of the compounds of this invention may beadministered orally, for example, with an inert diluent or with anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theaforesaid compounds may be incorporated with excipients and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gums and the like. These preparations should contain atleast 0.5% of active compound, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of active compound in such compositionsis such that a suitable dosage will be obtained. Preferred compositionsand preparations according to the present invention are prepared so thatan oral dosage unit form contains between 1.0 and 300 milligrams of theactive compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragancanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Promogel™, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring. When the dosage unit form is a capsule, it maycontain, in addition to materials of the preceeding type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit suchas, for example, coatings. Thus, tablets or pills may be coated withsugar, shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose and/or other sweeteningagents, preservatives, dyes, coloring agents and/or flavorings.Materials used in preparing these various compositions should bepharmaceutically pure and nontoxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of this invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 50% of the weightthereof. The amount of active compounds in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 and 100 miligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite,chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates; and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention. Unless otherwise indicated, withthe exception of yields which are calculated on a molar basis, all partsand percentages provided in these Examples are by volume.

EXAMPLE 11,2,3,4,5,6-Hexahydro-8-methoxy-1,3-dimethyl-2,6-dimethyl-1,3-benzodiazocinStep 1

To a stirred suspension of 172 g of potassium carbonate and 51.9 g of3-(5-hydroxy-2-nitrophenyl)propenoic acid in 1.6 l of gently refluxingacetone was added, dropwise, 65.5 g of dimethylsulfate. The resultingmixture was refluxed overnight, cooled, filtered and concentrated. Theconcentrate was washed with cold methanol and dried to afford3-(5-methoxy-2-nitrophenyl)-1-propenoic acid, methyl ester.

Step 2

To a stirred, chilled (ice bath) solution of 32.7 g of3-(5-hydroxy-2-nitrophenyl)propenoic acid, methyl ester and 300 g ofammonium acetate in 700 ml of tetrahydrofuran was added 840 ml oftitanium trichloride solution (20% in water). The resulting mixture wasbasified by the addition of about 1 kg of a 50% sodium hydroxidesolution and diluted with ethyl acetate. The aqueous phase was separatedand extracted with ethyl acetate. The combined organic phases werewashed with saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and concentrated to afford3-(5-methoxy-2-aminophenyl)-1-propenoic acid, methyl ester.

Step 3

To a stirred, chilled (0° C.) suspension of 49.0 g of3-(5-hydroxy-2-aminophenyl)propenoic acid, methyl ester and 47.4 g ofpolyvinylpyridine in 475 ml of dichloromethane was added, dropwise, 39.2g of ethyl malonyl chloride. After stirring at 0° C. for 0.5 hour themixture was filtered and concentrated to afford3-[[2-[(methoxycarbonyl)ethenyl]-4-methoxyphenyl]amino]-3-oxopropanoicacid, ethyl ester.

Step 4

To a stirred, chilled (0° C.) suspension of crude3-[[2-[(methoxycarbonyl)ethenyl]-4-methoxyphenyl]amino]-3-oxopropanoicacid, ethyl ester from step 3 in 700 ml of methanol was added, dropwise,a solution of 66.5 g of sodium methoxide (25% in methanol) in 250 ml ofmethanol. The resulting mixture was heated to reflux over 0.75 hour,cooled to 0° C., and poured into a cold saturated ammonium chloridesolution. The aqueous layer was extracted with dichloromethane and thecombined organic layers were washed with 10% hydrochloric acid solutionand saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford1,2,3,4-tetrahydro-6-methoxy-3-(methoxycarbonyl)-2-oxo-4-quinolineacetic acid, methyl ester.

A mixture of 67.0 g of1,2,3,4-tetrahydro-6-methoxy-3-(methoxycarbonyl)-2-oxo-4-quinolineacetic acid, methyl ester and 13 g of sodium chloride in 23 ml of waterand 300 ml of dimethyl sulfoxide was heated at 155° C. for 6 hours,cooled, and diluted with 1.2 l of a 1:1 mixture of ethyl acetate andwater. The aqueous phase was separated and extracted with ethyl acetate,and the combined organic layers were washed with water and saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,filtered, and concentrated to afford1,2,3,4-tetrahydro-6-methoxy-2-oxo-4-quinoline acetic acid, methylester.

Step 6

A solution of 40.8 g of 1,2,3,4-tetrahydro-6-methoxy-2-oxo-4-quinolineacetic acid, methyl ester in 500 ml of dimethyl formamide was added over1 hour to a chilled (0° C.) suspension of 4.6 g of sodium hydride in 300ml of dimethyl formamide. After stirring for 1 hour at ambienttemperature, 27.5 g of methyl iodide was added and the mixture stirredfor an additional hour. The mixture was then quenched with saturatedammonium chloride solution and extracted with ethyl acetate. Thecombined organic layers were washed with water and brine, dried overmagnesium sulfate, filtered and concentrated to an oil. Columnchromatography on silica gel (elution with hexane-ethyl acetate)afforded 1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinoline aceticacid, methyl ester.

Step 7

Lithium borohydride (100 ml of a 2.0M solution in tetrahydrofuran) wasadded to a solution of 34.6 g of1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinoline acetic acid,methyl ester in 330 ml of tetrahydrofuran. The mixture was stirred atroom temperature for 84 hours, cooled to 0° C., quenched with 10%aqueous hydrochloric acid, and concentrated. The aqueous layer wasbasified with potassium carbonate and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated to afford3,4-dihydro-4-(2-hydroxyethyl)-6-methoxy-1-methyl-2(1H)-quinolinone.

Step 8

To a chilled (0° C.) solution of 69 ml of pyridine in 600 ml ofdichloromethane was added 42.5 g of chromium trioxide. The resultingmixture was stirred at room temperature for 0.5 hour and a solution of10.0 g of3,4-dihydro-4-(2-hydroxyethyl)-6-methoxy-1-methyl-2(1H)-quinolinone in100 ml of dichloromethane was added, dropwise. The reaction mixture wasstirred for 0.5 hour, the solvent was decanted, and the resultingresidue washed with dichloromethane. The combined organic layers werewashed with 5% sodium hydroxide solution, 10% hydrochloric acidsolution, water, and brine, dried over anhydrous magnesium sulfate,filtered and concentrated. The resulting oil was filtered through silica(elution with ethyl acetate) and concentrated to afford1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinolineacetaldehyde.

Step 9

Sodium cyanoborohydride (1.2 g) was added to a solution of 10.0 g ofmethylamine hydrochloride and 4.6 g of1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinolineacetaldehyde in142 ml of methanol. The solution was stirred at room temperature for 19hours, quenched with 10% hydrochloric acid solution and extracted withethyl acetate. The aqueous layer was basified with potassium hydroxideand the product extracted into ethyl acetate. The combined organiclayers were washed with saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered and concentrated to an oil. Columnchromatography on silica gel (elution with triethylamine-methanol-ethylacetate) afforded3,4-dihydro-6-methoxy-1-methyl-4-[2-(methylamino)ethyl]-2(1H)-quinolinoneas a solid. To a solution of the amine in methanol was added etherealhydrochloric acid to pH 1. The solvent was removed, and the residuerecrystallized from isopropanol-diethyl ether to afford thehydrochloride salt, m.p. 175°-177° C.

Analysis: Calculated for C₁₄ H₂ N₂₀ O₂ •HCl: 59.05% C; 7.43% H; 9.84% N.Found: 58.90% C; 7.38% H; 9.78% N.

Step 10

To a stirred solution of 4.50 g of3,4-dihydro-6-methoxy-1-methyl-4-[2-(methylamino)ethyl]-2(1H)-quinolinonein 450 ml of refluxing n-butanol was added, incrementally over a periodof 1.5 hours, 27.0 g of sodium. The resulting mixture was stirred atreflux until all of the sodium was consumed, and then it was cooled, anddiluted with water. The aqueous phase was separated and extracted withethyl acetate. The combined organic layers were washed with water and asaturated aqueous solution of sodium chloride, dried over magnesiumsulfate, filtered, and concentrated. The concentrate was purified bymeans of column chromatography on silica gel (elution withtriethylamine/methanol/ethyl acetate) followed by recrystallization fromdiethyl ether-pentane to afford 2.20 g (52%) of1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine,m.p. 72°-73.5° C.

Analysis: Calculated for C₁₄ H₂₀ N₂ O: 72.38% C; 8.68% H; 12.05% N.Found: 72.30% C; 8.87% H; 12.16% N.

EXAMPLE 21,2,3,4,5,6-Hexahydro-8-methoxy-1-methyl-3-(1-phenylethyl)-2,6-methano-1,3-benzodiazocinefumarate

3,4-Dihydro-6-methoxy-1-methyl-4-[2-[(1-phenylethyl)amino]ethyl]-2(1H)-quinolinonewas prepared in a manner similar to the procedure set forth in Steps 1to 9 of Example 1.

To a stirred solution of 3.65 g of3,4-dihydro-6-methoxy-1-methyl-4-[2-[(1-phenylethyl)amino]ethyl]-2(1H)-quinolinonein 270 ml of refluxing n-butanol was added, incrementally over a periodof 1.5 hours, 7.40 g of sodium. The resulting mixture was stirred atreflux until all of the sodium was consumed, and then was cooled, anddiluted with water. The aqueous phase was separated and extracted withethyl acetate. The combined organic phase was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The concentrate waspurified by means of column chromatography on silica gel (elution withtriethylamine/methanol/ethyl acetate) to afford 2.04 g (59%) of1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-2-(1-phenylethyl)-2,6-methano-1,3-benzodiazocineas an oil.

To a solution of 1.83 g of the oil in diethyl ether was added 0.69 g offumaric acid in methanol. The solvent was removed in vacuo, and theresidual solid was recrystallized from methanol-diethyl ether to afford1.96 g of1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-3-(1-phenylethyl)-2,6-methano-1,3-benzodiazocinefumarate, m.p. 148°-151° C. (dec.).

Analysis: Calculated for C₂₁ H₂₆ N₂ O: 68.47% C; 6.89% H; 6.39% N.Found: 68.24% C; 6.89% H; 6.28% N.

EXAMPLE 31,2,3,4,5,6-Hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olfumarate

Boron tribromide solution (1.0M in dichloromethane, 0.10 mol, 100 ml)was added dropwise over one hour to a chilled (-78° C.) degassedsolution of 7.45 g of1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine in 220 ml of dichloromethane. The reaction mixture was warmed to 0°C. over one hour and then stirred at 0° C. for an additional hour. Themixture was then quenched with a saturated aqueous solution of sodiumcarbonate. The aqueous layer was further basified with potassiumcarbonate and the product extracted into dichloromethane. The combinedorganic layers were washed with a saturated aqueous solution of sodiumchloride, dried over potassium carbonate, filtered, and concentrated toafford 5.68 g of1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,as a solid.

The solid was suspended in 25 ml of methanol and treated with a solutionof 3.3 g of fumaric acid in 25 ml of hot methanol to precipitate thecorresponding fumarate salt. Trituration of the precipitate with hotmethanol afforded 4.3 g of1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olfumarate, m.p. 160°-166° C. (dec).

Analysis: Calculated for C₁₃ H₁₈ N₂ O•C₄ H₄ O₄ : 61.07% C; 6.63% H;8.38% N. Found: 60.82% C; 6.69% H; 8.26% N.

EXAMPLE 43-(Cylopropylmethyl)-1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-2,6-methano-1,3-benzodiazocine

4-[2-[(Cyclopropylmethyl)amino]ethyl]-3,4-dihydro-6-methoxy-1-methyl-2(1H)-quinolinonewas prepared in a manner similar to the procedure set forth in steps 1to 9 of Example 1.

To a stirred solution to 5.3 g of4,[2-[(cyclopropylmethyl)amino]-3,4-dihydro-6-methoxy-1-methyl-2(1H)quinolinonein 400 ml of refluxing n-butanol was added, incrementally over a periodof one hour, 12.7 g of sodium. The resulting mixture was stirred atreflux until all of the sodium was consumed, and then was cooled anddiluted with water. The aqueous phase was separated and extracted withethyl acetate. The combined organic phase was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate, filtered and concentrated. The concentrate waspurified by means of column chromatography on silica gel (elution withtriethylamine/hexanes/ethyl acetate) to afford3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-2,6-methano-1,3-benzodiazocineas an oil. Kugelhrohr distillation of the oil afforded 2.2 g ofanalytically pure product.

Analysis: Calculated for C₁₇ H₂₄ N₂ O: 74.96% C; 8.88% H; 10.28% N.Found: 74.79% C; 8.82% H; 10.08% N.

EXAMPLE 51,2,3,4,5,6-Hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olacetate, fumarate

A catalytic amount, (0.019 g) of N,N-dimethylaminopyridine was added toa deoxygenated solution of 5.8 g of1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-oland 5.4 g of acetic anhydride in 270 ml of dichloromethane. Afterstirring for 15 minutes, the reaction mixture was treated with asaturated sodium bicarbonate solution. The aqueous layer was separatedand extracted with dichloromethane. The combined organic layers werewashed with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered and concentrated to an oil (7.1 g). Columnchloromatography of a 3.5 g aliquot of the oil (silica gel; elution withtriethylamine-methanol-ethyl acetate) afforded 2.2 g of1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olacetate as a solid.

The solid product was dissolved in hot methanol, treated with fumaricacid (1.08 g) and concentrated. Treatment of the concentrate withdiethyl ether precipitated 2.5 g of the corresponding fumarate, m.p.183°-184° C. (dec.).

Analysis: Calculated for C₁₅ H₂₀ N₂ O₂ •C₄ H₄ O₄ : 60.63% C; 6.43% H;7.44% N. Found: 60.51% C; 6.47% H; 7.47% N.

EXAMPLE 610-Bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olacetate, salicylate

N-Bromosuccinimide (2.40 g) was added in three portions to a solution of3.50 g of crude1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olacetate in 135 ml of deoxygenated methanol. The resulting solution wasstirred at room temperature for five minutes and then diluted withdichloromethane and a saturated sodium bicarbonate solution. The aqueousphase was separated and extracted with dichloromethane, and the combinedorganic layers were washed with saturated sodium chloride solution,dried over anhydrous magnesium sulfate, filtered, and concentrated to anoil. Column chromatography of the oil (silica gel elution withtriethylamine-methanol-ethyl acetate) afforded 1.80 g (33%) of10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocine-8-olacetate as a solid.

The solid product was dissolved in methanol and treated with 0.72 g ofsalicyclic acid in diethyl ether. Concentration afforded a foam, whichwas crystallized from dichloromethane-pentane and then recrystallizedfrom methanol to provide 1.24 g of10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olacetate, salicylate, m.p. 168°-169° C.

Analysis: Calculated for C₁₅ H₁₉ BrN₂ O₂ •C₇ H₆ O₃ : 55.36% C; 5.28% H;5.87% N. Found: 55.45% C; 5.24% H; 5.81% N.

EXAMPLE 710-Bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,hemi-fumarate

A deoxygenated suspension of 3.59 g of10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olacetate and 2.90 g of potassium carbonate in 50 ml of 20% aqueousmethanol was stirred at ambient temperature for 15 minutes and thendiluted with water and dichloromethane. The aqueous layer was separatedand extracted with dichloromethane. The combined organic phases werewashed with saturated sodium chloride solution, dried over potassiumcarbonate, filtered and concentrated. The concentrate was suspended in30 ml of methanol, treated with a solution of 0.87 g of fumaric acid in25 ml of hot methanol, and heated briefly. Cooling to ambienttemperature precipitated 1.2 g (32%) of10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazodin-8-ol,hemi-fumarate, m.p. 195°-200° (dec.).

Analysis: Calculated for C₁₃ H₁₇ N₂ O•1/2C₄ H₄ O₄ : 50.72% C; 5.39% H;7.89% N. Found: 50.61% C; 5.44% H; 7.89% N.

EXAMPLE 81,2,3,4,5,6-Hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,cyclohexyl carbamate

Triisopropylsilyltrifluoromethane sulfonate (9.90 g) was added dropwiseto a 0° C. deoxygenated solution of 2,6-lutidene (6.66 g) and1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol(5.43 g) in dichloromethane under nitrogen. The resulting solution wasstirred at 0° C. for 3 hours, and then it was diluted with water andextracted into dichloromethane. The combined organic layers were washedwith brine, dried over magnesium sulfate, filtered, and concentrated toafford 12.1 of an oil. Column chromatography on silica gel (elution withtriethylamine-methanol-ethyl acetate) afforded 5.5 g of the desiredsilyl ether.

To the above silyl ether (2.5 g) in 67 mol of tetrahydrofuran at roomtemperature was added tetra-n-butyl ammonium fluoride solution (1M intetrahydrofuran, 6.68 ml). The resulting solution was stirred at roomtemperature for 15 min., and then lithium chloride (2.8 g) was added andthe mixture stirred for 5 minutes as the lithium chloride dissolved.Cyclohexyl isocyanate (0.91 g) was added to the above solution, and themixture was stirred for 18 hours, then quenched with water. The layerswere separated and the aqueous phase was extracted with dichloromethane.The combined organic layers were washed with saturated sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated toafford 2.2 g of crude product. Column chromatography on silica gel(elution with triethylamine-methanol-ethyl acetate) provided 1.36 g of afoam. This sample was combined with an additional 0.8 g of product andchromatographed on alumina (elution with triethylamine-ethyl acetate) togive 2.02 g of1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodrazocin-8-ol,cyclohexyl carbamate as a foam, m.p. 50°-60° C.

Analysis: Calculated for C₂₀ H₂₉ N₃ O₂ : 69.94% C; 8.51% H; 12.23% N.Found: 69.35% C; 8.69% H; 11.64% N.

EXAMPLE 91,2,3,4,5,6-Hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol,methyl carbamate fumarate

Triisopropylsilyltrifluoromethane sulfonate (9.90 g) was added dropwiseto a 0° C. deoxygenated solution of 2,6-lutidene (6.66 g) and1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol(5.43 g) in dichloromethane under nitrogen. The resulting solution wasstirred at 0° C. for 3 hours, and then it was diluted with water andextracted into dichloromethane. The combined organic layers were washedwith brine, dried over magnesium sulfate, filtered, and concentrated toafford 12.1 g of an oil. Column chromatography on silica gel (elutionwith triethylamine-methanol-ethyl acetate) afforded 5.6 g of the desiredsilyl ether.

To the above silyl ether (2.4 g) in 64 m of tetrahydrofuran at roomtemperature was added tetra-n-butyl ammonium fluoride solution (1M intetrahydrofuran, 6.4 ml). The resulting solution was stirred at roomtemperature for 15 minutes and then lithium chloride (2.7 g) was added,and the mixture stirred for 5 minutes as the lithium chloride dissolved.Methylisocyanate (0.39 g) was added to the above solution, and themixture was stirred for 18 hours then quenched with water. The layerswere separated and the aqueous phase was extracted with dichloromethane.The combined organic layers were washed with saturated sodium chloridesolution, dried over magnesium sulfate, filtered, and concentrated toafford 2.2 g of crude product. Column chromatography on silica gel(elution with triethylamine-methanol-ethyl acetate) provided 0.75 g of afoam.

The carbamate was dissolved in hot methanol and 0.316 g of fumaric acidwere added. Diethyl ether was then added and the mixture was allowed tocool. Filtration afforded 700 mg of a solid which was recrystallizedfrom methanol-diethyl ether, affording 0.45 g of1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-olmethyl carbamate fumarate.

Analysis: Calculated for C₁₉ H₂₅ N₃ O₆ : 58.30% C; 6.44% H; 10.73% N.Found: 58.42% C; 6.75% H; 10.59% N.

EXAMPLE 10 [2S-[2b,6b]] and[2R-[2a,6a]]-1,2,3,4,5,6-Hexahydro-2,6-methano-1,3-benzodiazocin-8-ol,S-α-methylbenzylcarbamate salicylate

Triisopropylsilyltrifluoromethane sulfonate (10.5 g) was added dropwiseto a 0° C. deoxygenated solution of 2,6-lutidene (7.06 g) and1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol(5.75 g) in dichloromethane (130 ml) under nitrogen. The resultingsolution was stirred at 0° C. for 3 hours, and then it was diluted withwater and extracted into dichloromethane. The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated to afford 14.5 g of an oil. Column chromatography on silicagel (elution with triethylamine-methanol-ethyl acetate) afforded 7.1 gof the desired silyl ether.

To the above silyl ether (6.63 g) in 75 ml of tetrahydrofuran at roomtemperature was added tetra-n-butyl ammonium fluoride solution (1M intetrahydrofuran, 17.7 ml). The resulting solution was stirred at roomtemperature for 15 minutes, and then lithium chloride (7.5 g) was added,and the mixture was stirred for 5 minutes as the lithium chloridedissolved. S-α-methylbenzylisocyanate (3.0 g) was added to the abovesolution, and the mixture was stirred for 18 hours, then quenched withwater. The layers were separated, and the aqueous phase was extractedwith dichloromethane. The combined organic layers were washed withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to afford 9.5 g of crude product. The oil waschromatographed twice (silica gel, elution withtriethylamine-methanol-ethyl acetate) to afford 3.5 g of the desiredproduct as a foam. Treatment of the foam in diethyl ether with anequivalent amount of salicylic acid in diethyl ether precipitated 3.1 gof [2S-[2b,6b]] and [2R-[2a,6a]]-1,2,3,4,5,6-Hexahydro-2,6-methano-1,3-benzodiazocin-8-ol,S-α-methylbenzylcarbamate salicylate, m.p. 95°-100° C.

Analysis: Calculated for C₂₉ H₃₃ N₃ O₅ : 69.17% C; 6.61% H; 8.34% N.Found: 68.57% C; 6.50% H; 8.40% N.

What is claimed is:
 1. A compound of the formula ##STR5## wherein R¹ isloweralkyl; R² and R³ are independently hydrogen, loweralkyl,cycloalkylloweralkyl, loweralkenyl or arylloweralkyl; the term "aryl"signifying a phenyl group optionally substituted by up to 3 substituentseach of which is independently loweralkyl, loweralkoxy, halogen,trifluoromethyl, nitro or cyano; and R⁴ and R⁵ are independentlyhydrogen or loweralkyl.